Authors' Affiliations: Biozentrum, University of Basel; Research Group Human Genetics, Dept of Biomedicine, University of Basel, and Division of Medical Genetics, University Hospital Basel; Institute for Surgical Research and Hospital Management and Department of Biomedicine, University of Basel; Institute of Pathology, University Hospital of Basel, Basel; Pathologie Laenggasse Bern, Bern; Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland; Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; and Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
Cancer Res. 2014 Jan 1;74(1):224-34. doi: 10.1158/0008-5472.CAN-13-2100. Epub 2013 Oct 24.
The genome-wide accumulation of DNA replication errors known as microsatellite instability (MSI) is the hallmark lesion of DNA mismatch repair (MMR)-deficient cancers. Although testing for MSI is widely used to guide clinical management, the contribution of MSI at distinct genic loci to the phenotype remains largely unexplored. Here, we report that a mononucleotide (T/U)16 tract located in the 3' untranslated region (3'-UTR) of the Ewing sarcoma breakpoint region 1 (EWSR1) gene is a novel MSI target locus that shows perfect sensitivity and specificity in detecting mismatch repair-deficient cancers in two independent populations. We further found a striking relocalization of the EWSR1 protein from nucleus to cytoplasm in MMR-deficient cancers and that the nonprotein-coding MSI target locus itself has a modulatory effect on EWSR1 gene expression through alternative 3' end processing of the EWSR1 gene. Our results point to a MSI target gene-specific effect in MMR-deficient cancers.
全基因组范围内 DNA 复制错误的积累，即微卫星不稳定性（MSI），是 DNA 错配修复（MMR）缺陷型癌症的标志性病变。虽然 MSI 检测被广泛用于指导临床管理，但特定基因座上的 MSI 对表型的贡献在很大程度上仍未得到探索。在这里，我们报告位于尤文肉瘤断点区域 1（EWSR1）基因 3'非翻译区（3'-UTR）中的一个单核苷酸（T/U）16 重复序列是一个新的 MSI 靶基因座，在两个独立的人群中检测 MMR 缺陷型癌症具有完美的敏感性和特异性。我们进一步发现，在 MMR 缺陷型癌症中 EWSR1 蛋白从细胞核重新定位到细胞质，并且非蛋白编码的 MSI 靶基因座本身通过 EWSR1 基因的选择性 3'末端加工对 EWSR1 基因表达具有调节作用。我们的研究结果表明，MSI 靶基因特异性效应在 MMR 缺陷型癌症中存在。
